Abstract 5501: An integrated end-to-end platform facilitating the evaluation of next generation KRAS inhibitors

Abstract Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated oncogene, and has attracted substantial attention in the preclinical arena. Over the last 40 years, KRAS has been deemed a challenging therapeutic target and has even been described as “undruggable” due to the intrinsic characteristics of KRAS proteins. This has resulted in an urgent and unmet clinical need to target KRAS mutations in KRAS-driven cancer. Recent advances have uncovered a new allosteric site of KRAS (G12C) that facilitates the development of novel covalent allosteric inhibitors targeting this shallow pocket on the surface of KRAS, thereby raising the hope of effectively drugging KRAS. Encouraging clinical trial results have been reported for two KRAS G12C inhibitors, AMG510 (sotorasib) and MRTX849 (adagrasib), with AMG510 being approved by the FDA for clinical use in 2021. Despite the clinical benefits of KRAS G12C inhibitors such as AMG510 and MRTX849, there are still problems that need to be overcome including optimization of clinical efficacy and overcoming drug resistance. Recent clinical research has identified diverse genomic and histological features underlying the resistance of KRAS G12C mutant cancer patients. These resistance mechanisms include co-occurring mutations such as KEAP1, SMARCA4 and CDKN2A, and the acquisition of genetic mutations such as H95D, H96D and R68S in the switch-II pockets. Other non-genetic mechanisms such as reactivation of RAF-MEK-ERK pathway and cell state transition have also been identified. To enable discovery of the new generation of KRAS inhibitors, we have developed a comprehensive KRAS assay platform, which includes biochemical and cell based in vitro assays, and in vivo efficacy evaluation in KRAS mutant xenograft models. In addition, to allow researchers to have a better understanding of the biological basis of drug resistance, we have established and validated a panel of lung and pancreatic cell models that are resistant to AMG510 and MRTX849 through CRISPR-Cas9 editing and drug-induced approaches. Our continuously evolving assay platform facilitates the discovery and development of new generation KRAS inhibitors and combinational strategies. Citation Format: Di Zhan, Lingling Huang, Lei Zhang, Ting Ma, Yuzhou Xu, Yinfei Yin, Zichun Wang. An integrated end-to-end platform facilitating the evaluation of next generation KRAS inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5501.